Gestational Diabetes Mellitus Alone in the Absence of Subsequent Diabetes Is Associated With Microalbuminuria: Results from the Kidney Early Evaluation Program (KEEP)

OBJECTIVE Women with gestational diabetes mellitus (GDM) maintain a higher risk for recurrent GDM and overt diabetes. Overt diabetes is a risk factor for development of chronic kidney disease (CKD), but GDM alone, without subsequent development of overt diabetes, may also pose a risk for CKD

Adenine crosses the biomarker bridge: from ‘omics to treatment in diabetic kidney disease

Enabling the early detection and prevention of diabetic kidney damage has potential to substantially reduce the global burden of kidney failure. There is a critical need for identification of mechanistic biomarkers that can predict progression and serve as therapeutic targets. In this issue of the JCI , Sharma and colleagues used an integrated multiomics approach to identify the metabolite adenine as a noninvasive biomarker of progression in early diabetic kidney disease (DKD). The highest tertile of urine adenine/creatinine ratio (UAdCR) was associated with higher risk for end-stage kidney disease and mortality across independent cohorts, including participants with early DKD without macroalbuminuria. Spatial metabolomics, single-cell transcriptomics, and experimental studies localized adenine to regions of tubular pathology and implicated the mTOR pathway in adenine-mediated tissue fibrosis. Inhibition of endogenous adenine production was protective in a diabetic model. These findings exemplify the potential for multiomics to uncover mechanistic biomarkers and targeted therapies in DKD

Definition, identification and treatment of resistant hypertension in chronic kidney disease patients

Resistant hypertension, the inability to achieve goal blood pressure despite the use of three or more appropriately dosed antihypertensive drugs (including a diuretic), remains a common clinical problem, especially in patients with chronic kidney disease (CKD). While the exact prevalence and prognosis of resistant hypertension in CKD patients remain unknown, resistant hypertension likely contributes significantly to increased cardiovascular risk and progression of kidney disease in this population. We review the identification and evaluation of patients with resistant hypertension, including the importance of 24-h ambulatory blood pressure monitoring in the identification of 'white-coat', 'masked' and 'non-dipper' hypertension, the latter of which has particular clinical and therapeutic importance in patients with resistant hypertension and CKD. We then discuss treatment strategies for resistant hypertension that target the pathophysiologic mechanisms underlying resistance to treatment, including persistent volume excess, incomplete renin-angiotensin-aldosterone system blockade and inadequate nocturnal blood pressure control. Finally, we propose a treatment algorithm for evaluation and treatment of resistant hypertension in patients with CKD

Aldosterone Blockade in Chronic Kidney Disease

Although blockade of the renin-angiotensin-aldosterone system with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers has become standard therapy for chronic kidney disease (CKD), renewed interest in the role of aldosterone in mediating the injuries and progressive insults of CKD has highlighted the potential role of treatments targeting the mineralocorticoid receptor (MR). Although salt restriction is an important component of mitigating the profibrotic effects of MR activation, a growing body of literature has shown that MR antagonists, spironolactone and eplerenone, can reduce proteinuria and blood pressure in patients at all stages of CKD. These agents carry a risk of hyperkalemia, but this risk likely can be predicted based on baseline renal function and mitigated using dietary modifications and adjustments of concomitant medications. Data on hard outcomes, such as progression to end-stage renal disease and overall mortality, still are lacking in patients with CKD. (C) 2014 Elsevier Inc. All rights reserved

Role of Sphingolipid Signaling in Glomerular Diseases: Focus on DKD and FSGS

Sphingolipids are well-recognized as major players in the pathogenesis of many human diseases, including chronic kidney disease. The kidney is a very sensitive organ to alterations in sphingolipid metabolism. The critical issues to be addressed in this review relate to the role of sphingolipids and enzymes involved in sphingolipid metabolism in the pathogenesis of glomerular diseases with a special focus on podocytes, a key cellular component of the glomerular filtration barrier. Among several sphingolipids, we will highlight the role of ceramide, sphingosine, sphingosine-1-phosphate and ceramide-1-phosphate. Additionally, we will summarize the current knowledge with regard to the use of sphingolipids as therapeutic agents for the treatment of podocyte injury in kidney disease

Sphingosine-1-Phosphate Metabolism and Signaling in Kidney Diseases

In the past few decades, sphingolipids and sphingolipid metabolites have gained attention because of their essential role in the pathogenesis and progression of kidney diseases. Studies in models of experimental and clinical nephropathies have described accumulation of sphingolipids and sphingolipid metabolites, and it has become clear that the intracellular sphingolipid composition of renal cells is an important determinant of renal function. Proper function of the glomerular filtration barrier depends heavily on the integrity of lipid rafts, which include sphingolipids as key components. In addition to contributing to the structural integrity of membranes, sphingolipid metabolites, such as sphingosine-1-phosphate (S1P), play important roles as second messengers regulating biologic processes, such as cell growth, differentiation, migration, and apoptosis. This review will focus on the role of S1P in renal cells and how aberrant extracellular and intracellular S1P signaling contributes to the pathogenesis and progression of kidney diseases

Aldosterone breakthrough during aliskiren, valsartan, and combination (aliskiren plus valsartan) therapy

Aldosterone levels increase in 30%-40% of patients on angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers over the long term. This "aldosterone breakthrough" may carry important clinical consequences given aldosterone's nonepithelial, pro-fibrotic actions. The renin inhibitor, aliskiren, by suppressing the renin-angiotensin-aldosterone system (RAAS) proximally, may limit breakthrough compared to conventional RAAS blockade. This open-label study (NCT01129557) randomized subjects to aliskiren 300 mg daily (A), valsartan 320 mg daily (V), or aliskiren 150 mg + valsartan 160 mg daily (A+V) for 9 months. Eligible subjects had proteinuria >300 mg/day, estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m(2), and systolic blood pressure (BP) >130 or diastolic BP >80 mm Hg. Serum and 24-hour urine aldosterone (indexed to 24-hour urine Na) were checked before initiation of therapy and at 3, 6, and 9 months. Aldosterone breakthrough was defined as a sustained increase from baseline aldosterone by study end. The study was intended to enroll 120 subjects but was terminated early by the sponsor. We present here the results of 33 subjects who completed the protocol, of which 12 were randomized to A, 11 were randomized to V, and 10 were randomized to A+V. Mean baseline eGFR was 75.5 (+/- 23.3) mL/min/1.73 m(2); baseline proteinuria was 3104 (+/- 2943) mg/day; and baseline BP was 134.7 (+/- 10.5)/84.8 (+/- 8.4) mm Hg. Three (27%) subjects on V, three (25%) subjects on A, and three (30%) subjects on A+V had aldosterone breakthrough. Mean proteinuria reduction was 31% from baseline in all subjects: 30% in subjects with breakthrough vs. 32% in subjects without breakthrough. Mean BP reduction was 11.0/8.8 mm Hg in all subjects: 8.4/6.1 mm Hg in subjects with breakthrough vs. 12.0/9.8 mm Hg in subjects without breakthrough. Aliskiren, alone or in combination with valsartan, did not reduce the incidence of aldosterone breakthrough in subjects with hypertension and proteinuria compared with conventional RAAS blockade. J Am Soc Hypertens 2012;6(5):338-345. (C) 2012 American Society of Hypertension. All rights reserved

Abstract P318: Blood Pressure And Cardiovascular Disease Mortality Among US Adults, 1999-2019

Introduction: Elevated blood pressure (BP) is recognized as the leading risk factor for cardiovascular disease (CVD). Low BP values are also markers of concurrent CVD. Our objective was to determine the association between systolic BP (SBP) and diastolic BP (DBP) with CVD mortality, comparing different BP ranges in a contemporaneous population. Methods: The National Health and Nutrition Examination Survey is a nationally representative survey of the US population. Our sample included data from 53,561 adult participants of the 1999-2018 cycles, with measured BP and mortality data available through 2019 linked from the National Death Index. BP was measured three times with a standardized sphygmomanometer and averaged. CVD mortality was defined through ICD-10 codes as diseases of the heart or cerebrovascular disease. We used age adjusted Poisson regression models to estimate incidence densities ratios (IDRs) for CVD mortality. All analyses accounted for the complex survey design. Results: The population was comprised of 51% women with a mean age of 46 years. After an average follow-up of 9.9 years, 7,825 (10.5%) died of any cause and 2,451 (3.1%) died of CVD. Compared with SBP 110 - < 120mmHg, CVD mortality did not differ at SBP 100-<100mmHg or 120-<130 mmHg, but was significantly higher by: 56% with SBP <100mmHg (IDR: 1.56, 95% CI: 1.15, 2.10), 21% with SBP 130 – < 140mmHg (IDR: 1.21, 95% CI: 1.04, 1.42), 36% with SBP 140 – < 160mmHg (IDR: 1.36, 95% CI: 1.14, 1.64), and 77% with SBP ≥160mmHg (IDR: 1.77, 95% CI: 1.47, 2.14). Compared with DBP 70 - < 80mmHg, CVD mortality was significantly higher by 64% with DBP < 50mmHg (IDR: 1.64, 95% CI: 1.38, 1.94), 46% with DBP 50 - < 60mmHg (IDR: 1.46, 95% CI: 1.26, 1.670), 24% with DBP 60 – < 70 mmHg (IDR: 1.24, 95% CI: 1.09, 1.41), 36% with DBP 80 – < 90mmHg (IDR: 1.36, 95% CI: 1.15, 1.61), 54% with DBP 90 – < 100mmHg (IDR: 1.54, 95% CI: 1.20, 1.97), and 182% with DBP ≥100mmHg (IDR: 2.82, 95% CI: 1.90, 4.19). Conclusion: Among US adults, we found a J shaped association between both SBP and DBP with CVD mortality. Lowest risk of CVD mortality was found at SBP 110 - < 120mmHg, with higher risk at levels below 100mmHg or at or above 130mmHg. For DBP, lowest risk of CVD mortality was found at DBP 70 - < 80mmHg, with higher risk at levels below 70mmHg or at or above 80mmHg

In Vitro Atrial Septal Ablation Using High-Intensity Focused Ultrasound

High-intensity focused ultrasound (HIFU) has been applied clinically as a noninvasive therapeutic tool. Atrial septostomy is a palliative treatment for pulmonary artery hypertension. The purpose of this study was to assess the feasibility of atrial septal ablation in vitro using HIFU. Fourteen sections of atrial septum from pig hearts were treated. Focused ultrasound energy was applied with an operating frequency of 5.25 MHz at the nominal focal point intensity of 4.0 kW/cm2 for 0.4 sec in 1-sec intervals. Lesions were created with ultrasonic exposures ranging from 40 to 120 pulses. There were significant relationships between HIFU exposure time and lesion area on the exposed site (R2 = 0.3389, P < .0001) and lesion volume (R2 = 0.6161, P < .0001). HIFU has the potential to create focal perforations without direct tissue contact. This method may prove useful for noninvasive atrial septostomy